The present invention relates to novel stereoisomeric indole compounds or salts therof, process for the preparation of the compounds and use of the compounds.
An indole compound (tartefragin A) of the following formula which is isolated from an extract of seaweed, xe2x80x9cAyanishikixe2x80x9d(Martensia fragilis Harvey) belonging to, Congregatocarpus family is known [Proceedings of Japan Pharmaceutical Society, the 116th annual meeting, page 2,215 (1996)]. 
Further, the above-mentioned indole compound is known to have an anti-oxidative action and to have uses including pharmaceutical ones. However, a synthetic method and stereochemistry of the above-mentioned indole compound was not known.
The inventors of the present invention tried first to synthesize stereoisomers of the above-mentioned compound in order to clarify stereostructure, physiological activities and action mechanisms etc. thereof. As a synthetic route for the stereoisomers of the compound, they noticed a route for synthesizing the following L-tryptophan (2) and a stereoisomeric xcex1-amino acid (3axe2x80x2) (hereinafter, the stereoisomeric xcex1-amino acid is referred to as homoisoleucine) as intermediates. 
(wherein, R, R1 and R2 have the meanings shown below, and the symbol xe2x80x98*xe2x80x99 represents a position of asymmetric carbon atom.)
Since the stereoisomers of the above-mentioned homoisoleucine are not commercially available compounds, they also established a synthetic route described below for the stereoisomers of the homoisoleucine, and furthermore they succeeded to synthesize a stereoisomeric indole compound (1axe2x80x2) from the above-mentioned L-tryptophan (2) and a stereoisomeric homoisoleucine (3axe2x80x2).
Further, from the fact that the synthetic route for the stereoisomeric indole compound (1axe2x80x2) from the above-mentioned L-tryptophan (2) and the stereoisomeric homoisoleucine (3axe2x80x2) was established, in the same manner as in the stereoisomeric homoisoleucine, novel indole alkaloids could be synthesized from L-tryptophan and various xcex1-amino acids other than the stereoisomeric homoisoleucine as starting materials for the purpose of searching compounds having stronger physiological activities than those of the above-mentioned compound (1axe2x80x2), thus many compounds was obtained.
The inventors also have found that a deamino form of the above-mentioned compound (1axe2x80x2) has higher inhibitory action against lipid peroxidation than any of the four isomers of the above-mentioned Martefragin A, that is (1xe2x80x3S,3xe2x80x3S) form, (1xe2x80x3R,3xe2x80x3S) form, (1xe2x80x3R,3xe2x80x3R) form and (1xe2x80x3S,3xe2x80x3R) form, and also have established synthetic routes thereof.
That is, the present invention relates to stereoisomeric indole compounds of the following formula (1) or salts thereof. 
wherein, Y represents the group: 
wherein, X represents alkyl group having 1-5 carbon atom(s) (the alkyl group may be optionally substituted with hydroxyl group, carboxyl group, amino group, methylthio group, mercapto group, guanidyl group, imidazolyl group or benzyl group), and R1 and R2 represent each independently hydrogen atom, alkyl group, aralkyl group, cycloalkyl group or aryl group, or Y represents the group 
R represents hydrogen atom, alkyl group, aralkyl group, cycloalkyl group, aryl group, monovalent metal atom, amine or ammonium; and the symbol xe2x80x98*xe2x80x99 represents a position of an asymmetric carbon atom.
Specifically, there may be mentioned the compound of an amino form of the formula (1a): 
or salts thereof as well as the compound of a deamino form of the compound of the formula (1a) of the formula (1b) or salts thereof 
wherein, R, R1, R2 and X have the same definitions as the formula (1)
In compounds of the above-mentioned formulae (1), (1a) and (1b), specific examples of suitable substituents are as follows.
In addition to the fact that the substituent R represents hydrogen atom, typical substituents R are straight chained or branched alkyl group having 1-12, particularly 1-6, carbon atom(s), such as methyl group, ethyl group, propyl group, isopropyl group, n-butyl group, tertiary butyl group, pentyl group, hexyl group, octyl group, decyl group and dodecyl group; cycloalkyl group having 5 or 6 ring carbon atoms, such as cyclopentyl group, methylcyclopentyl group, cyclohexyl group and methylcyclohexyl group; aryl group having 6-16 carbon atoms and aralkyl group having 7-16 carbon atoms, such as phenyl group, naphthyl group, benzyl group and phenylethyl group, which may be substituted with halogen atom, hydroxyl group, alkoxy group, amino group and so on. Further, the substituent R may be monovalent metal such as sodium and potassium, amine or ammonium.
Further, suitable substituents R1 and R2 are straight chained or branched alkyl group having 1-12, particularly 1-6, carbon atom(s), such as methyl group, ethyl group, propyl group, isopropyl group, n-butyl group, tertiary butyl group, pentyl group, hexyl group, octyl group, decyl group and dodecyl group; cycloalkyl group having 5 or 6 ring carbon atoms, such as cyclopentyl group, methylcyclopentyl group, cyclohexyl group and methylcyclohexyl group; aryl group having 6-16 carbon atoms and aralkyl group having 7-16 carbon atoms, such as phenyl group, naphthyl group, benzyl group and phenylethyl group, which may be substituted with halogen atom, hydroxyl group, alkoxy group, amino group and so on.
As the salts of the compounds of the formulae (1), (1a) and (1b), there are exemplified salts of inorganic acids and organic acids. However, hydrochloride are particularly preferable.
The indole compounds according to the present invention have one or more asymmetric carbon atom(s), thus form or R form isomers occur depending upon the positions) thereof. For example, in the case of an amino form of the compound (1axe2x80x2), 
it has asymmetric carbon atoms at positions 1xe2x80x3 and 3xe2x80x3. Therefore, the compounds according to the invention have four isomers respectively for their asymmetric carbon atoms, i.e., (1xe2x80x3S,3xe2x80x3S) form, (1xe2x80x3R,3xe2x80x3S) form, (1xe2x80x3R,3xe2x80x3R) form, (1xe2x80x3S,3xe2x80x3R) form. Further, a deamino form (1b) 
of the indole compound according to the invention has an asymmetric carbon atom at position 3xe2x80x3. Therefore, the compounds according to the invention have two isomers respectively for their asymmetric carbon atoms, i.e., S form and R form.
The present invention includes all these isomers and mixtures of the isomers.
In the following illustration, the indole compound of the above-mentioned formula (1b) is also referred to as xe2x80x9cdeaminomartefraginxe2x80x9d.
The present invention also relates to a process for preparing the stereoisomeric indole compounds of the following formula (1) 
by condensing tryptophan of the following formula (2) 
with an acid of the following formula (3) 
to obtain a compound of the following formula (4), 
and subjecting the compound of the formula (4) to cyclization,
wherein, Y represents the group 
wherein, X represents alkyl group having 1-5 carbon atom(s) (the alkyl group may be substituted with hydroxyl group, carboxyl group, amino group, methylthio group, mercapto group, guanidyl group, imidazolyl group or benzyl group), and R1 and R2 represent each independently hydrogen atom, alkyl group, aralkyl group, cycloalkyl group or aryl group, or Y represents the group 
R represents hydrogen atom, alkyl group, aralkyl group, cycloalkyl group, aryl group, monovalent metal atom, amine or ammonium; and the symbol xe2x80x98*xe2x80x99 represents a position of an asymmetric carbon atom.
According to this method, the amino form of the stereoisomeric indole compound of the above-mentioned formula (1a) can be prepared by condensing tryptophan of the above-mentioned formula (2) with an acid of the formula (3a) 
to obtain a compound of the following formula (4a), 
and subjecting the compound of the formula (4a) to cyclization, and the deamino form of the stereoisomeric indole compound of the above-mentioned formula (1b) can be prepared by condensing tryptophan of the above-mentioned formula (2) with an acid of the following formula (3b) 
to obtain a compound of the following formula (4b), 
and subjecting the compound of the formula (4b) to cyclization, wherein, R, R1, R2 and X have the above-mentioned meanings.
In the compounds of the above-mentioned formulae (2)-(4), (2a)-(4a) and (2b)-(4b), specific examples of suitable substituents are same as those mentioned for the formulae (1), (1a) and (1b).
As described above, the acid used for synthesis of the stereoisomeric indole compounds according to the invention is a stereoisomeric xcex1-amino acid in the case of preparing an amino form and also 4-methylhexanoic acid which is a stereoisomeric carboxylic acid in case of preparing a deamino form.
Typical stereoisomeric xcex1-amino acids include, for example, four stereoisomers of (+)alanine, (+)valine, (xe2x88x92) leucine, (+)isoleucine, (+)lysine, (xe2x88x92)serine, (xe2x88x92)threonine, (xe2x88x92)phenylalanine, (xe2x88x92)tyrosine, (xe2x88x92)aspartic acid, (+)glutamic acid, (xe2x88x92)methionine, (+)arginine, (xe2x88x92)histidine, (+)ornithine, (+)norleucine, (+)oxyglutamic acid, (xe2x88x92)cysteine and homoisoleucine. Note that four stereoisomers of hoxnoisoleucine are not commercially available, and their synthetic examples are shown below in I. Preparation Examples 1-4 for amino forms of stereoisomeric indole compounds.
4-Methylhexanoic acid has two isomers, which are obtained respectively as intermediates in a synthetic route for (2S,4S)-homoisoleucine in the Preparation Example I and in a synthetic route for (2S,4R)-homoisoleucine in the Preparation example 3 described below.
According to the invention, a stereoisomeric indole compound is prepared by (1) condensing tryptophan with a stereoisomeric xcex1-amino acid or 4-methylhexanoic acid to form an amide, and then (2) subjecting the amide to oxidative cyclization to form an oxazole ring at once by a novel synthetic method For condensation of the tryptophan with the stereoisomeric xcex1-amino acid or 4-methylhexanoic acid, it is preferable to protect an amino group of the xcex1-amino acid. Although there may be mentioned dialkylatione preferably dimethylation, t-butoxycarbonylation and so on for protection of the amino group, it is preferable that when the protecting group being t-butoxycarbonyl group (Boc group) because, particularly, condensation of tryptophan with the stereoisomeric xcex1-amino acid and the subsequent cyclization of the amide are proceeded efficiently.
Further, if the oxidative cyclization of the amide is carried out particularly in the presence of 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ), the cyclization is proceeded efficiently to obtain the cyclized form in a high yield.
For the compounds of the formula (1) according to the invention, it is possible to obtain various kinds of compounds by varying the group Y according to selection of raw materials, i.e., a stereoisomeric xcex1-amino acid and a carboxylic acid, and by varying the substituents R, R1 and R2 according to selection of ester group in the raw material, i.e., tryptophan ester, and selection of the amino substituent of the stereoisomeric xcex1-amino acid, or by changing the substituents in the compounds after synthesis with other substituents R, R1 and R2 different from those.
The novel stereoisomeric indole compounds according to the invention are alkaloids having an indole ring and an oxazole ring, which have inhibitory action against lipid peroxidation, and can be therefore utilized as preventing drugs and therapeutic drugs for circulatory disorders such as arteriosclerosis, hypertension, thrombosis; inflammations such as nephritis; hepatic disorders such as alcoholic hepatitis; digestive disorders such as gastric ulcer; diabetes, carcinogenesis and senescence as well as ultraviolet disorders, and also utilized as ultraviolet disorder preventing materials in cosmetics and the like.
Therefore, the present invention furthermore relates to lipid peroxidation inhibitors containing as the active ingredient the stereoisomeric indole compounds or their salts which are of the above-mentioned formula (1) and exemplified by the formulae (1a) and (1b).
Synthetic examples of amino forms of indole compounds according to the invention are illustrated as follows. Before synthesis for the compounds according to the invention, syntheses for stereoisomeric homoisoleucine which is raw materials are illustrated in Preparation Examples 1-4, and synthetic examples for stereoisomeric indole compounds by using them are illustrated in Examples
(2S,4S)-homolsoleucine can be synthesized from optically active methylbutanol or optically active methyliodobutane as starting materials. 
1. Tosylation of optically active methylbutanol (step 1 in Scheme 1)
1 g (11.3 mmol) of (S)-2-methyl-1-butanol: (S)-1 (Tokyo Kasei) and 30 ml of anhydrous pyridine are added into a 100 ml egg plant type flask under an argon atmosphere and stirred at 0xc2x0 C., and thereafter 4.31 g (22.6 mmol) of p-toluenesulfonyl chloride is added and stirred at 0xc2x0 C. for 30 minutes, and then stirred at room temperature for 5 hours. Ice water is added and an aqueous layer is adjusted to pH 2-3 with 3N hydrochloric acid and then extracted with diethyl ether. After it is washed with a saturated sodium hydrogencarbonate solution and a saturated saline solution, dried with anhydrous magnesium sulfate, and distilled off the solvent under a reduced pressure, to obtain a colorless oily substance. It is purified with a column chromatography (75 g of SiO2, hexane/ethyl acetate=10:1), to obtain 2.5 g of a tosylated form (S)-2 (a colorless oily substance: yield; 91.41).
C12H18SO3 (M.W.; 242.10), a colorless oily substance, [xcex1]n20+5.66 (C=1.060, MeOH)
2. Iodation of tosylated form (S)-2 (step 2 in Scheme 1)
1.94 g (S mmol) of the tosylated form (S)-2 and 30 ml of anhydrous acetone are added into a 100 ml egg plant type flask under an argon atmosphere, shielded from light, and thereafter 2.4 g (16 mmol) of sodium iodide is added. After stirring at room temperature for 2 days, pentane is added to dilute the reaction solution and cooled to precipitate its sodium salt. After the sodium salt is removed with a glass filter, it is extracted with water to remove acetone, dried with anhydrous magnesium sulfate and distilled off pentane under the normal pressure, to obtain 1.08 g (yield; 68.0%) of an iodated form (S)-3. The structure thereof is confirmed by comparison with a commercially available one.
3. Synthesis of ester malonate using iodated form (S)-3 (step 3 in Scheme 1)
1.38 g of metallic sodium and 50 ml of anhydrous ethanol are added into a 200 ml three-necked flask under an argon atmosphere at 0xc2x0 C. and stirred. After sodium is all dissolved, 9.45 ml of diethyl malonate is added dropwise by a syringe, and then 6.5 ml of the iodated form (S)-3 is added dropwise and stirred at room temperature overnight. 100 ml of an aqueous ammonium chloride solution is added, ethanol is removed by distillation under a reduced pressure, and the residue is extracted with diethyl ether. An ether layer is washed with a saturated saline solution, thereafter dried with anhydrous magnesium sulfate, and distilled off the solvent under a reduced pressure, to obtain a colorless oily substance, It is purified with a column chromatography (200 g of SiO2 for flash, hexane/ethyl acetate 30:1), to obtain 8.80 g (yield; 76.5%) of a diester form (S)-4.
C12H22O4 (M.W.; 230.15), a colorless oily substance, [xcex1]D2+15.3 (C=1.060, MeOH)
4. Hydrolysis of diester form (S)-4 (step 4 in Scheme 1)
6.90 g of the diester form (S)-4 and 20 ml of ethanol are added into a 300 ml egg plant type flask and stirred. 5.71 g (102 mmol) of potassium hydroxide dissolved beforehand in 100 ml of water is added and heated at reflux. The temperature of the solution is returned to room temperature and ethanol is removed by distillation under a reduced pressure, and thereafter impurities are removed by extraction with ethyl acetate. After 3N HCl is added to an aqueous layer to adjust to pH 1-2, the layer is extracted with ethyl acetate. An organic layer is salted out with sodium chloride, dried with anhydrous magnesium sulfate and thereafter distilled off the solvent under a reduced pressure, to obtain 5.22 g (yield; 100%) of an intended compound, a dicarboxylic acid (S)-5.
C8H14O4 (M.W.; 174.09), white powders, [xcex1]D26+16.9 (C=1.10, MeOH)
5. Decarboxylation of dicarboxylic acid (S)-5 (step 5 in Scheme 1)
5.05 g (29 mmol) of the dicarboxylic acid (S)-5, 16 ml of a 7% aqueous DMSO solution and 1.87 g (32 mmol) of sodium chloride are added into a 50 ml egg plant type Cask, and heated at 150-175xc2x0 C. for 4 hours. The temperature of the solution is returned to room temperature and extracted twice with diethyl ether, and an organic layer is washed with water. It is dried with anhydrous magnesium sulfate and distilled off the solvent under a reduced pressurer to obtain a colorless oily substance. It is purified with a column chromatography (120 g of SiO2, pentane/diethyl ether=5:1), to obtain 2.82 g (yield; 75%) of an intended carboxylic acid (S)-6. The (S)-6 is a raw material for synthesis of deaminomartefragin described below.
C7H14O2 (M.W.; 130.10), colorless and oily, [xcex1]D26+9.69 (C=1.042, MeOH)
6. Synthesis of acid chloride (S)-7 (step 6 in Scheme 1)
2.82 g of the carboxylic acid (S)-6, 18.0 ml of anhydrous benzene and 9.0 ml of thionyl chloride are added into a 50 ml egg plant type flask and heated at reflux for 3 hours. The temperature of the solution is returned to room temperature and thereafter distilled off the solvent under a reduced pressure, to obtain 2.92 g (yield; 91%) of an acid chloride (S)-7. The (S)-7 is subjected to condensation with an asymmetrical assistant group (S)-8 without any purification after confirming absorption of the carbonyl group assigned to the acid chloride by IR spectrum. C7H13Cl (M.W.; 148.55), colorless and oily.
7. Condensation with asymmetic assistant group (S)-8 (step 7 in Scheme 1)
3.85 g (21.7 mmol) of (4S)-benzyloxazolidinone and 50 ml of anhydrous (THF) are added into a 200 ml three-necked flask under an argon atmosphere and cooled to xe2x88x9278xc2x0 C. 13.6 ml of a 1.6M n-butyl lithium/n-hexane solution is added and stirred at xe2x88x9278xc2x0 C. for 40 minutes, and 2.92 g (19.7 mmol) of the acid chloride (S)-7 is added and stirred at xe2x88x9278xc2x0 C. for 1.5 hours. An aqueous ammonium chloride solution is added, and the solution is extracted with diethyl ether, washed with a saturated saline solution, dried with anhydrous magnesium sulfate, and thereafter distilled off the solvent under a reduced pressure, to obtain a colorless oily substance. It is purified with a column chromatography (45 g of SiO2, hexane/ethyl acetate=5:1), to obtain 4.93 g (yield; 86.5%) of an intended compound (S)-9, as colorless crystals.
C17H23NO3 (M.W.; 289.29), white powders, [xcex1]D27+59.3 (C=1.088, CHCl3)
8. Direct azidation to carboxyimide (step 8 in Scheme 1)
1.03 g (5.19 mmol) of potassium ditrimethylsilylamide and 10 ml of anhydrous THF are added into a 100 ml two-necked flask under an argon atmosphere and made to xe2x88x9278xc2x0 C. 1 g (3.46 mmol) of (S)-9 dissolved beforehand in 10 ml of anhydrous THF is added by a cannula and stirred at xe2x88x9278xc2x0 C. for 30 minutes. Furthermore, 1.35 g (4.36 mmol) of triisopropyl benzenesulfonylazide dissolved beforehand in 6 ml of anhydrous THF is added by a cannula and stirred for 2 minutes, and thereafter 0.91 ml (15.9 mmol) of glacial acetic acid is added. It is stirred at room temperature for 7 hours. The reaction solution is diluted with ethyl acetate, to which a saturated saline solution is added and extracted twice with ethyl acetate. It is washed with a saturated sodium hydrogencarbonate, dried with anhydrous sodium sulfate, and distilled off the solvent under a reduced pressure, to obtain 1.85 g of a yellow oily substance. It is purified with a column chromatography (60 g of SiO2. for flash, hexane/dichloromethane=3:1), to obtain 893 mg (yield; 78.1%) of an intended azide form (2S, 4S)-10.
C17H22N4O3 (M.W.; 330.39), colorless crystals, mp.; 71.5-72.5xc2x0 C., [xcex1]D24+112.2 (C=1.032, CHCl3)
9. Removal of asymmetrical assitant group [Synthesis of xcex1-azide carboxylic Acid (2S, 4S-11] (step 9 in Scheme 1)
850 mg of the azide form (2S, 4S)-10 and 50 ml of 75% THF are added into a 200 ml egg plant type flask under an argon atmosphere and made to 0xc2x0 C., and 216 mg of lithium hydroxide monohydrate is added and stirred for 1 hour. An aqueous saturated sodium hydrogencarbonate solution is added, distilled off THF under a reduced pressure, and thereafter extracted with ethyl acetate. An ethyl acetate layer is dried with anhydrous sodium sulfate and distilled off the solvent under a reduced pressure, to recover 450 mg (yield; 99%) of (S)-8. An aqueous layer is adjust to pH 1-2 with 3N hydrochloric acid and extracted with ethyl acetate, and an ethyl acetate layer is dried with anhydrous sodium sulfate and distilled off the solvent under a reduced pressure, to obtain 425 mg (yield; 96.7%) of an intended xcex1-azide carboxylic acid (2S,4S)-11 as an colorless oily substance.
C7H13N3O2 (M.W.; 171.101), a colorless oily substance, [xcex1]D23+3.26 (C=0.982, CHCl3)
10. Reduction of xcex1-azide carboxylic acid: Synthesis of (2S,4S)-homoisolencine (step 10 in Scheme 1)
378 mg (2.21 mmol) of the xcex1-azide carboxylic acid (2S,4S)-11, 4.0 ml of anhydrous ethanol and 37.8 mg of 10% Pd-C are added into a 25 ml egg plant type flask under an argon atmosphere with hydrogen displacement and stirred at room temperature for 2.5 hours. Pd-C is removed by filtration and the solvent is distilled off under a reduced pressure, to obtain 285 mg (yield; 88.9%) of (2S,4S)-12 [(2S,4S)-homoisoleucine] as colorless crystals.
C7H15NO2 (M.W.; 145.1103), colorless crystals, IR: xcexd [cmxe2x88x92]=2962, 2920, 1584, 1513, 1405, 669, 554, 471 LREIMS: m/z (%) 154(M+, 1), 100(100) HREIMS Calcd for C7H15NO2: 145.1103, Found 145.1127
The steps to the acid chloride (S)-7 are the same as the above-mentioned Preparation Example 1. The asymmetrical assistant group used has R-configuration. The reaction steps after the condensation with the asymmetrical assistant group are carried out similarly to Preparation Example 1. The reaction steps from the condensation with the asymmetrical assistant group to synthesis of (2R,4S)-homoisoleucine [(2R,4S)-23] and physical data for (2R,4S)-homoisoleucine are shown as follows. 
(2S,4R)-homoisoleucine is synthesized from (S)-citronellol as a starting material. 
1. Mesylation of (S)-citronellol (step 1 in Scheme 3)
5 g (32.0 mmol) of (5)-citronellol, 180 ml of dichloromethane and 4.86 g (35.2 mmol, 1.1 eq) of triethylamine are added into a 500 ml three-necked flask under an argon atmosphere and cooled with ice to xe2x88x9210xc2x0 C., and thereafter 4.03 g (35.2 mmol, 1.1 eq) of mesyl chloride is added dropwise. After the reaction solution is stirred at xe2x88x9210 to 0xc2x0 C. for 2.5 hours, it is washed with ice water, 5% hydrochloric acid and water, dried with anhydrous sodium sulfate and distilled off the solvent under a reduced pressure, to obtain a colorless oily substance (S)-30. It is subjected to the next reduction without any purification.
2. Reduction of mesylate (S)-30 (step 2 in Scheme 3)
400 ml of diethyl ether and 1.80 g (47.3 mmol, 1.4 eq) of lithium aluminum hydride are added into a 200 ml three-necked flask equipped with a calcium chloride tube and a reflux condenser and cooled with ice. A solution of 7.92 g (33.8 mmol) of (S)-30 in diethyl ether is added dropwise and heated at reflux for 3 hours. After completion of the reaction, the reaction solution is cooled with ice, and 3.6 ml of water is added and stirred for 1 hour, additional 2.88 ml of a 10% aqueous sodium hydroxide solution is added and stirred for 1 hour thereafter filtered off by Celite to remove lithium aluminum hydride and distilled off the solvent under a reduced pressure, to obtain 4.5 g (98%) of a colorless oily substance (R)-31.
3. Oxidation of (R)-31 (step 3 in Scheme 3)
24.7 g (115.6 mmol, 3.6 eq) of sodium periodate and 175 ml of an aqueous acetone solution (acetone:water=70:105) are added to suspend in a 500 ml three-necked flask under an argon atmosphere. A solution of 4.5 g (32.1 mmol) of (R)-31 in acetone is added dropwise and made to 5xc2x0 C. 40 ml of a solution of 0.86 g (5.46 mmol, 0.17 eq) of potassium permanganate in water and 40 ml of acetone are added dropwise simultaneously. They are stirred at from 5xc2x0 C. to room temperature for 20 hours. A reddish brown residue is removed by filtration with Celite, and acetone is distilled off under the normal pressure. 1N sodium hydroxide is added to the residue to make basic, which is extracted with diethyl ether to remove solubles. An aqueous layer is acidified with 3N hydrochloric acid, extracted with diethyl ether, dried with anhydrous sodium sulfate and distilled off the solvent under a reduced pressure, to obtain a colorless oily substance. It is purified with a column chromatography (50 g of SiO2, hexane/ethyl acetate=5:1), to obtain 2.389 g (57%) of (R)-32. The (R)-32 is a raw material for synthesis of deaminomartefragin described below.
4. Steps (4)-(8) in Scheme 3
Steps (4)-(8) in Scheme 3 are carried out similarly to steps (6)-(10) in Preparation Example 1. Physical data of the obtained (2S,4R)-homoisoleucine [(2S,4R)-37] are as follows. 
IR (neat): v [cmxe2x88x921]=2964, 1587, 1404
Steps to the acid chloride (R)-33 are same as the above-mentioned Preparation Example 3. The steps after the condensation with an asymmetric assistant group by using R-configuration asymmetric assistant group are carried out similar to the Preparation Example 1.
The steps from the condensation with the asymmetrical assistant group to synthesis of (2R,4R)-homoisoleucine [(2R,4R)-47] and physical data for (2R4R)-homoisoleucine are shown as follows. 